Kommunikation mellan celler är avgörande för utvecklingen av en multicellulär organism. För att kunna växa och skapa vävnader måste cellerna hela tiden skicka och ta emot signaler. Celler som inte är i direkt kontakt med varandra, är inbäddade i en extracellulär matrix som signalmolekyler måste transporteras igenom. Kompositionen av extracellulär matrix, som bland annat innehåller många proteoglykaner påverkar informationsöverföringen. Proteoglykaner är proteiner modifierade med sulfaterade sockerkedjor. Många enzymer är inblandade i att polymerisera och modifiera proteoglykaner. Sulfatgrupper som sitter på sockerkedjorna ger proteoglykaner en hög negativ laddning vilket binder många andra proteiner och attraherar vatten, vilket är nödvändigt för mekaniskt stöd i broskvävnader. För att bättre förstå hur många olika typer av sockerkedjor som kan produceras och hur de interagerar med proteiner i olika vävnader, använder vi oss av zebrafiskar som modell.
I vårt arbete fokuserade vi på heparansulfat (HS) proteoglykaner och chondroitin/dermatansulfat (CS/DS) proteoglykaner. För att studera funktionen av HS och CS/DS biosyntes använde vi oss av zebrafiskar som saknar utvalda enzymer nödvändiga för uppbyggnaden av dessa sockerkedjor. I vissa mutanter fann vi morfologiska förändringar i broskstrukturer och efter biokemiska analyser kunde vi se att HS och CS/DS samspelar i uppbyggandet av broskstrukturer (arbete I). Lite var känt om CS/DS biosyntes i zebrafisk, därför beslöt vi att identifiera zebrafiskgener som motsvarar tidigare identifierade gener inblandade i CS/DS biosyntes hos däggdjur.
Vi beskrev först alla CS/DS syntetiserande enzymer och studerade dess uttrycksmönster hos unga zebrafiskar (arbete II). Vi fortsatte sedan med att beskriva grupper av modifieringsenzymer för HS och CS/DS som inte tidigare analyserats (arbete III och IV). Dessa studier ger oss nu en full bild av var och när GAG biosyntesenzymer är uttryckta. Överlappande uttryck av vissa glykosyltransferaser stödjer tidigare hypoteser om att dessa enzymer agerar tillsammans för att polymerisera sockerkedjor.
I sista delarbetet använde vi oss av den nya CRISPR/Cas9-tekniken för att skapa mutationer i HS och CS/DS biosyntesenzymer hos zebrafiskar (arbete V). CRISPR/Cas9-tekniken möjliggör en effektiv och riktad mutagenes hos zebrafiskar, vilket inte var genomförbart tidigare. Man använder sig av en kort RNA-molekyl som vägleder Cas9, ett nuklease, till en specifik sekvens i
genomet för att klippa båda DNA strängarna. Cellernas egen reparationsmekanism är felbenägen och därför introduceras det ofta en deletion eller insertion när strängbrottet repareras. Med denna metod har vi nu skapat mutationer i 17 olika gener och de flesta fiskar som vi har undersökt hittills har överlevt som homozygota mutanter till vuxen ålder utan att utveckla uppenbara morfologiska förändringar. Detta tyder på att dessa enzymer har överlappande funktioner och att flera gener måste slås ut hos en och samma fisk för att kunna studera enskilda enzymatiska modifikationer. Vi har nu ett antal nya zebrafiskmutanter tillgängliga för vidare morfologiska och biokemiska studier. Med dessa hoppas vi kunna få större inblick i den funktionella rollen av GAG biosyntesenzymer under zebrafiskens utveckling.
Acknowledgements
I would like to express my sincere gratitude to all co-workers, co-authors and collaborators, who have helped me throughout my years and contributed to this work.
My first and very special thank you goes to you, Johan, my supervisor and true Doktorvater. I am forever grateful that you gave me the chance to work with you;
you taught me so much in so many different ways. You have been a true scientific father to me, and even with the physical distance over the past two years, we developed a great way to work together, skype was our friend. I am also thankful that I got the chance to come and work with you at the NIH. Thank you for always meeting me with open arms, keeping up with my emotional ups and downs, spreading your passion for GAGs and zebrafish, mediating your wisdom in science and life, and for being in the same boat with me for such a long time. Dankeschön!
Thank you, Per, my co-supervisor for giving me the opportunity to work in this great group and giving me advice and guidance along the way, and thank you for your great spirit not only at work, but also on christmas-party-dancefloors.
Thank you so much, Katarina. Who needs Olivia, if I have you? You have always been there for me, fixed things for me, helped me out in the lab and with the thesis and other written texts; your input is very valuable to me. You really lived through all my ups and downs in our cozy office and you have been guiding me and pushing me forward. I am endlessly thankful for our friendship, co-authorships, common passion for zebrafish, GAGs and Scandal. Without you I wouldn’t be here at all.
Thank you to all the people from the Ahlberg Lab, and fikagänget, for the great discussions related to work and everything else, fantastic cakes and all the fun moments and laughter, you are all so lavish to me. Thank you Helena and Rose-Marie, for all the help in the lab and with administrative things. Thank you Tatjana for collaborations and your help in the lab and with my thesis. Special thanks to you,
Beata, for the fun times working together, all the collaborations and great discussions at and outside work. Thank you for your friendship!
Thank you also to everyone from IMBIM, who I worked with over the years. My scientific path started out with you. Thank you Johan K., Dorothe and Lena for guidance and advice, Inger for your great HPLC wisdom and help, and Anna for sharing your lab bench and knowledge with me for my HPLC preparation.
Thank you to everyone I met at the NIH in Bethesda for your warm welcome and help. Special thank you to you Shawn, for your open door, our discussions, your kindness, and your immense knowledge. Big thank you also to you, Gaurav, for everything you told me, the trust you have in me, your sharing of reagents and experience. I felt immediately welcome in the lab.
Thanks
With a friend by your side, no road seems too long.
No matter how many words I put on these pages, I am afraid they wont be able to cover the gratitude I feel, the emotions inside me, and the people that were part of this very special journey in my life. Still, I want to try, because if you never try, you will never know.
I thank honestly everyone, who is or was part of my life. Some of you had a bigger, some a smaller influence on me, but without every single one of you, I wouldn’t be where I am today.
Thank you to all my friends here and there, in the fish, in the volleyball and in the mountains. Thank you for always being by my side, even after knowing crazy me and the drama queen inside me. Volleyball is a big part of my life and I am very grateful for every encounter I made over the years, indoor and in the sand. Thank you so much for making my life better, funnier, full of laughter and love.
Meine gonzen Freinde in meiner scheanen Heimat bin i a volle donkbor. Es hob net so viel live mitkriag von meiner Dokotorzeit, obor enkre Besuche, die Heimaturlaube, die Berge de mir bestiegen hoben und die Feste de mir gfeiert hoben, hoben mir die Energie geben olm wieder weiterzugian. Danke dafür!
A riesiges Danekschön an meine Familie. Liebe Mami, lieber Papi, danke, dass es olm und überoll für mi do seid, es fohrts mir noch in die weite Welt und unterstützt mi olm a wenn i wirklich oft net leicht bin. Enkre Ratschläge und weisen Worte helfen mir viel und den drhoam des es für ins gschofft hob hon i mein gonzes Leben zu verdanken. Hannes, mein Bruderherz, du bringsch mi nach wie vor af die Palme wia mit 14 obor i war nix und niamand ohne di. Du bisch olm hinter mir gstonden und hosch Sochen für mi af di Fiass gstellt de i dir nia vergessen wear.
Danke vielmals! Sonja mit dir hot dr Hannes an guaten Fong gemocht und i bin froa um de Bereicherung in insrer Famile. Danke für olles wos du für mi getun hosch und du Ellen, hosch mir nu an richitgen Freudenkick geben is leschte Stickl nu zu gian.
Last but not least, thank you Carl, my better half. You have been supporting me throughout the years, even in the hard times in the end. I am forever grateful that you are by my side, in guten wie in schlechten Tagen. Danke für deine unendliche Liebe. Du bisch mein Fels in der Brandung.
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